PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism

Metabolic reprogramming is a hallmark of cancer, including lung cancer. However, the exact underlying mechanism and therapeutic potential are largely unknown. Here we report that protein arginine methyltransferase 6 (PRMT6) is highly expressed in lung cancer and is required for cell metabolism, tumorigenicity, and cisplatin response of lung cancer. PRMT6 regulated the oxidative pentose phosphate pathway (PPP) flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phospho-gluconate dehydrogenase (6PGD) and α-enolase (ENO1). Furthermore, PRMT6 methylated R324 of 6PGD to enhancing its activity; while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate (2-PG) binding to ENO1, respectively. Lastly, targeting PRMT6 blocked the oxidative PPP flux, glycolysis pathway, and tumor growth, as well as enhanced the anti-tumor effects of cisplatin in lung cancer. Together, this study demonstrates that PRMT6 acts as a post-translational modification (PTM) regulator of glucose metabolism, which leads to the pathogenesis of lung cancer. It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

Case analysis of a patient with osimertinib-induced interstitial pneumonia who re-used EGFR-TKI therapy / 中国药房

OBJECTIVE To explore the way to re-use epidermal growth factor receptor-tyrosine kinase inhibitors （EGFR-TKI） in patients with EGFR-TKI-induced interstitial pneumonia （IP）， using osimertinib as an example. METHODS The IP treatment regimen and re-use of EGFR-TKI regimen in a patient who developed IP after the use of osimertinib were analyzed. And a literature review was made by combining the characteristics of the cases which reported in the literature and the characteristics of this case. RESULTS The patient’s IP symptoms due to treatment with osimertinib had resolved after treatment. The patient’s IP symptoms also did not worsen after using almonertinib in combination with hormones as re-use of EGFR-TKI regimen. However， almonertinib was discontinued as the patient experienced disease progression. The adverse reactions of IP needed to be dealt with in time， the EGFR-TKI should be discontinued and symptomatic treatment should be given. CONCLUSIONS EGFR-TKI targeted therapy could be re-selected by replacing EGFR-TKI， adjusting the dose of EGFR-TKI， and using hormones in combination. EGFR-TKI-induced adverse drug reactions of IP are rare， but need to be observed closely. If other EGFR-TKI is used， close monitoring of adverse reactions and curative effects are also required in order to adjust the patient’s treatment plan in time.

Research progress of IRE1α inhibitors / 药学学报

Inositol requiring enzyme 1 alpha (IRE1α), a widespread transmembrane protein in mammals, is an endoplasmic reticulum stress (ER stress) receptor. Among the three signaling pathways of the unfolded protein response (UPR), the IRE1α pathway is the most conservative. And there is a growing body of evidence that the occurrence and development of tumors is closely related to the over-expression of IRE1α. Therefore, the study of the IRE1α inhibitors is of great significance to the discovery of new anti-tumor drugs and has been attracting more and more attention. In the hope of providing ideas for the research of targeting IRE1α for cancer therapy, this paper reviewed the data of representative IRE1α inhibitors, including inhibitory activity, the mechanism of action, structural characteristics, and so on.

Establishment and evaluation of a predictive model for clinical remission of advanced esophageal squamous cell carcinoma after neoadjuvant chemotherapy / 中国胸心血管外科临床杂志

@#Objective     To investigate the influencing factors for the clinical remission of advanced esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemotherapy, establish an individualized nomogram model to predict the clinical remission of advanced ESCC with neoadjuvant chemotherapy and evaluate its efficacy, providing serve for the preoperative adjuvant treatment of ESCC. Methods     The clinical data of patients with esophageal cancer who underwent neoadjuvant chemotherapy (nedaplatin 80 mg/m2, day 3+docetaxel 75 mg/m2, day 1, 2 cycles, 21 days per cycle interval) in the Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College from February 2016 to August 2020 were analyzed retrospectively. According to the WHO criteria for efficacy assessment of solid tumors, tumors were divided into complete remission (CR), partial remission (PR), stable disease (SD) and progressive disease (PD). CR and PR were defined as effective neoadjuvant chemotherapy, and SD and PD were defined as ineffective neoadjuvant chemotherapy. Univariate and multivariate analyses were used to analyze the influencing factors for the short-term efficacy of neoadjuvant chemotherapy. The R software was used to establish a nomogram model for predicting of the model. C-index, calibration curve and receiver operating characteristic (ROC) curve were used to evaluate the predictive performance of the nomogram. Results     Finally 115 patients were enrolled, including 93 males and 22 females, aged 40-75 (64.0±8.0) years. After receiving docetaxel+nedaplatin neoadjuvant chemotherapy for 2 cycles, there were 9 patients with CR, 56 patients with PR, 43 patients with SD and 7 patients with PD. Among them, chemotherapy was effective (CR+PR) in 65 patients and ineffective (SD+PD) in 50 patients, with the clinical effective rate of about 56.5%(65/115). Univariate analysis showed that there were statistical differences in smoking history, alcoholism history, tumor location, tumor differentiation degree, and cN stage before chemotherapy between the effective neoadjuvant chemotherapy group and the ineffective neoadjuvant chemotherapy group (P<0.05). Logistic regression analysis showed that low-differentiation advanced ESCC had the worst clinical response to neoadjuvant chemotherapy, moderately-highly differentiated ESCC responded better (P<0.05). Stage cN0 advanced ESCC responded better to neoadjuvant chemotherapy than stage cN1 and cN2 (P<0.05). The C-index and the area under the ROC curve of the nomogram were both 0.763 (95%CI 0.676-0.850), the calibration curve fit well, the best critical value of the nomogram calculated by the Youden index was 70.04 points, and the sensitivity and specificity of the critical value were 80.0% and 58.0%, respectively. Conclusion    The established clinical prediction model has good discrimination and accuracy, and can provide a reference for individualized analysis of the clinical remission of advanced ESCC with neoadjuvant chemotherapy and the screening of new adjuvant treatment subjects.

Relationship between the SUV max of primary lesion on 18F-FAPI-42 PET/CT imaging and the clinicopathological characteristics of patients with gastric cancer / 中华核医学与分子影像杂志

Objective:To explore the relationship between 18F-fibroblast activation protein inhibitor (FAPI)-42 SUV max of primary gastric cancer and clinicopathological factors of patients. Methods:Fifty-one patients (31males, 20 females, age: 51(47, 65) years) with gastric cancer who underwent 18F-FAPI-42 PET/CT before surgical resection in Nanfang Hospital, Southern Medical University from February 2022 to January 2023 were analyzed retrospectively. The clinicopathological factors that might affect tumor SUV max (including gender, age, tumor location, pathological type, histological grade, Lauren classification, vascular and(or) neural invasion, programmed cell death-ligand 1 (PD-L1) expression, pathologic(p)T stage, pN stage and pTNM stage) were evaluated by the univariate analysis (Mann-Whitney U test or Kruskal-Wallis rank sum test) and multivariate analysis (multiple linear regression analysis). Results:The sensitivity of 18F-FAPI-42 PET/CT in the diagnosis of patients with primary gastric cancer was 82.35% (42/51). The diagnostic sensitivities for early gastric cancer (T1) and locally advanced gastric cancer (T2-T4) were 59.09%(13/22) and 100%(29/29), respectively. The SUV max of primary lesion was 4.90(1.71, 12.51). The univariate analysis showed that SUV max of primary gastric cancer was related to tumor location ( z=-2.00, P=0.046), pT stage ( H=36.94, P<0.001), pN stage ( z=-3.89, P<0.001), pTNM stage ( H=31.49, P<0.001) and vascular and(or) nerve invasion ( z=-5.22, P<0.001), but not related to pathological type, histological grade, Lauren typing, and PD-L1 expression ( z values: from -1.78 to -0.09, all P>0.05). pT stage was found to be a significant independent factor for SUV max in primary gastric lesion by multivariate analysis ( t=2.52, P=0.015). Conclusions:The 18F-FAPI-42 SUV max of primary tumor was related to tumor location, pT stage, pN stage, pTNM stage, and vascular and(or) nerve invasion; pT stage is an independent factor affecting tumor SUV max. The ability of 18F-FAPI-42 PET/CT to detect gastric cancer is mainly affected by pT stage.

Types of ulnar styloid process fracture and treatment of distal radius fracture / 中华创伤骨科杂志

Objective:To investigate the effects of types of ulnar styloid process fracture on the treatment of distal radius fracture.Methods:The 80 patients were analyzed retrospectively who had been treated at The First Department of Hand Surgery, Honghui Hospital from January 2019 to January 2020 for fracture of distal radius complicated with fracture of ulnar styloid process. They were 25 males and 55 females, aged from 30 to 85 years (average, 58.6 years). According to the types of ulnar styloid process fracture, 40 patients were assigned into a Hauck type Ⅰ group and the other 40 into a Hauck type Ⅱ group. The 2 groups were compared in terms of operation, postoperative complications, hospital stay, bone union, visual analogue scale (VAS) on postoperative 1 to 3 days, and modified Mayo wrist function score, wrist range of motion and quality of life by WHOQOL-BREF at the last follow-up.Results:The 2 groups were comparable because there was no significant difference in age, gender, American Society of Anesthesiologists (ASA) rating, or time from injury to operation between them ( P>0.05). All the patients were followed up for 12 to 24 months (average, 17 months). There was no significant difference between Hauck type Ⅰ group and Hauck type Ⅱ group in operation time, intraoperative blood loss, hospital stay, rate of postoperative complications, fracture union, modified Mayo wrist function score or VAS on postoperative 1 to 3 days ( P>0.05). At the last follow-up, the palm tilt and ulnar inclination angles were 13.8°±1.9° and 21.6°±2.8° in Hauck type Ⅰ group, significantly larger than those in Hauck type Ⅱ group (11.9°±1.6° and 18.8°±2.3°) ( P<0.05). At the last follow-up, Hauck Ⅰ group scored 85.3±6.4,85.6±6.5, 84.7±6.3 and 85.0±6.7 respectively in the domains of physical health, psychology, environment and social relationships, significantly higher than those Hauck type Ⅱ group did (78.5±6.5, 78.9±6.5, 77.8±6.1 and 77.9±6.3) ( P<0.05). Conclusions:In open reduction and internal fixation for distal radius fracture, Hauck Type Ⅰ fracture of ulnar styloid process has no significant effect on the functional recovery of the wrist but Hauck Type Ⅱ fracture of ulnar styloid process may. Therefore, surgical fixation needs to be strengthened if Hauck Type Ⅱ fracture of ulnar styloid process is complicated.

Fundus changes presented by OCT and OCTA after scleral buckling for rhegmatogenous retinal detachment / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To observe the changes of the morphology and structure of macula, blood flow density of macula and optic disc, as well as retinal nerve fiber layer thickness by optical coherence tomography(OCT)and optical coherence tomography angiography(OCTA)in patients with rhegmatogenous retinal detachment(RRD)under went sclera buckling(SB). METHODS: As a cross-sectional case-controlled study, 25 patients(25 eyes)were diagnosed with RRD in the department of ophthalmology, Ganzhou People's Hospital from July 2014 to March 2021. The differences in the vascular density(VD)of superficial vessel cluster(SVC), the VD of deep vessel cluster(DVC)of macula, the SVC-VD of optic disc, retinal nerve fiber layer(RNFL), central macular thickness(CMT), subfoveal choroidal thickness(SFCT)and outer structure of macula between the affected eyes and healthy eyes at the last post-operative follow-up were compared, and the correlation indicators affecting best corrected visual acuity(BCVA, LogMAR)of the affected eyes at the last follow-up were analyzed. RESULTS: There were no statistically significant in SVC-VD and DVC-VD of macula, SVC-VD of optic disc, RNFL, CMT, SFCT between the affected eyes and healthy eyes at the last post-operative follow-up(all P&#x003E;0.05); At the last follow-up visit, the comparison of macular outer structure on OCT between the affected eyes and the healthy eyes showed that the light band integrity of the external limiting membrane(ELM), myoid zone(MZ), ellipsoid zone(EZ)and outer segment of photoreceptor(OS)had no statistically significant difference(all P&#x003E;0.05), while the light band integrity of interdigitation zone(IZ)had significant difference(P=0.014); The difference of BCVA(LogMAR)between the affected eyes and the healthy eyes at the last follow-up was statistically significant(P=0.002). There was significant correlation between BCVA(LogMAR)of affected eyes at the last post-operative follow-up and the presence or absence of macular involvement, the correlated with SVC-VD of optic disc, the integrity of the light bands of ELM, MZ, EZ, OS and IZ on the outer structure of macula, it was positively correlated with the presence or absence of macular involvement(rs=0.401, P=0.047)and it was negatively correlated with SVC-VD of optic disc, the integrity of the light bands of ELM, MZ, EZ, OS and IZ on the outer structure of macula(all P&#x003C;0.05).CONCLUSION: The OCT and OCTA can be used to observe fundus changes after SB surgery for RRD to obtain long-term follow-up information related to vision prognosis, and visual prognosis depends on the recovery of retinal outer structure, and the integrity of IZ structure is more important for visual recovery; The SVC-VD of optic disc is correlated with visual prognosis, and whether it was correlated with intraocular pressure require further observation and verification with postoperative continuous data.

A novel robotic-assistant flexible ureteroscopy system: initial results from the in vitro study and the in vivo experience / 中华泌尿外科杂志

Objective:Objectives The aim of the study is to evaluate the mechanical performance, safety and efficacy of the novel robotic-assistant flexible ureteroscopy system (Ra-fURS) under in vitro and in vivo environments.Methods:Combing with commercial flexible ureteroscopes, the novel Ra-fURS was used for the in vitro test and animal model operation in October 2020. The study included three sections. ①Basic mechanical performance assessment: including endoscope motion control (dual deflection, axial rotation and forward/backward distance), reaction time and fiber regulation. ②Simulated surgery in ex-vivo 3D-printing renal collecting system model: including completion rate and time of calyxes exploration, directional movement and laser fragmentation [gypsum models (0.5×0.5×0.5 cm) were used to stimulate kidney stones]. ③Intrarenal surgeries in animal models (two 5-month female Yorkshire white pigs). In total, 32 surgeries was performed (8 surgeons × 2 pigs × 2 kidneys/pig). In vivo assessments were carried out including: ①consuming time for Ra-fURS installation and offloading; ②completion rate and time of calyxes exploration; ③comfort score (ranging from 0-10) as compared to the manual f-URS, which was corresponding to each Ra-fURS surgery. In simulated surgery and animal surgery sections, 8 surgeons were enrolled in the study (group A 4 without flexible ureteroscopy experience; group B: 4 highly experienced), and results were compared between two groups.Results:Under the Ra-fURS control, the flexible ureteroscope movement in three degrees of freedom (forward / backward: + 11 to -11 cm, axial rotation + 225°to -225°; active duel-flection: + 270°to -270°, as well as the laser fiber regulation + 2.5 to -2.5 cm). In simulated surgery tests, both groups achieved 100% completion rate of calyxes exploration, and there were no statistical differences in the time of the calyxes exploration between group A and group B (116.0±8.0)s vs.(110.3±15.4)s( P>0.05). Time-consumption for laser fragmentation of group B was shorter than that of group A (525.8±58.5)s vs. (780.5±141.2)s( P<0.01). In animal surgery, the installation time of Ra-fURS gradually shortened within the first 7 cases was(234.0±43.0)s, and became comparable in the later 8-32 cases was(149.3±8.0)s. The average uninstall time was (43.9 ±5.9)s and was relatively stable. There were 51 renal calyxes in two pigs. It was higher for the completion rate of calyxes exploration in group B than in group A [(95.5±9.1)% vs. (59.1±9.1)%, P<0.05], and the exploration time was also statistically variant between the two groups group A and group B[(274.8±34.6)s vs.(127.3±18.2)s, P<0.05]. For all the operators, the comfort scores were favorable to the Ra-fURS as compared to the manual f-URS (8.9±0.3 vs. 5.9±1.1, P<0.05). Conclusions:This preliminary study demonstrated that the novel Ra-fURS was capable of controlling flexible ureteroscope to perform retrograde intrarenal surgery and fragmenting stones with laser. Besides, other features, including easy installation, stable performance and comfortable manipulating environment, made it easy to use in clinical application.

Clinical value of sleep characteristics in distinguishing mild cognitive impairment from Alzheimer′s disease / 中国医师杂志

Objective:To observe the sleep characteristics of mild cognitive impairment (MCI) patients and Alzheimer disease (AD) patients, and to evaluate their values in distinguishing MCI and AD.Methods:50 patients with MCI and 50 patients with AD diagnosed in Hangzhou Seventh People′s Hospital from June 2020 to March 2022 were recruited in this study. All-night polysomnography (PSG) was performed for each patient. The total sleep time (TST) , proportion of sleep structure (N1%, N2%, N3%, REM%) , sleep efficiency (SE), sleep latency (SL), rapid eye movement sleep latency (REML), wake time after sleep onset (WASO), sleep spindle density (ρ spindle) and sleep k-complex density (ρ KC) were compared between the two groups. The indexes of sleep characteristics with statistical significance between the two groups were included to perform logistic stepwise regression. The single-factorial and multi-factorial prediction models were established. Receiver operating characteristic (ROC) curve was used to compare the value of single-factorial model and multi-factorial model in distinguishing MCI and AD patients. Results:There were statistically significant difference in TST, N3, SE, ρ spindle between MCI and AD groups ( t=3.315, 2.798, 3.682, 6.488, all P<0.05). Logistic stepwise regression analysis showed that N3, SE, ρ spindle was included in the modeling portfolio, and the joint prediction model was Logit (pre)=-19.972-0.269N3-0.141SE-3.303 ρ spindle. The sensitivity of N3, SE, ρ spindle and multi-factorial model for distinguishing MCI and AD was 64%, 32%, 96%, 90%, and the specificity was 58%, 98%, 50%, 76%, respectively. The area under the ROC curve (AUC) of the multi-factorial model and multi-factorial model were 0.639, 0.684, 0.810 and 0.901, respectively. The AUC of multi-factorial model was significantly better than that of single-factorial models ( P<0.05). Conclusions:In AD suspected population, the multi-factorial prediction model based on N3, SE and ρ spindle has a certain predictive value in distinguishing MCI and AD. Comprehensive judgment combined with the prediction model is helpful to improve the scientificity and accuracy of diagnosis.

Hippocampus is involved in 17β-estradiol exacerbating experimental occlusal inter- ference-induced chronic masseter hyperalgesia in ovariectomized rats / 北京大学学报(医学版)

OBJECTIVE@#To investigate the influence of chronic masseter hyperalgesia induced by 17β-estradiol (E2) and experimental occlusal interference (EOI) on underlying mechanism in hippocampus of ovariectomized (OVX) rats.@*METHODS@#In the study, 32 OVX rats were randomly divided into 4 groups (8 rats/group): The control group was OVX group, and 0 μg/d E2 (vehicle) injection was started 7 d after OVX without EOI; in the experimental group (1) OVX + E2 group, 80 μg/d E2 injection was started 7 d after OVX without EOI; in the experimental group (2) OVX + EOI group, vehicle injection was started 7 d after OVX and EOI was applied 17 d after OVX; in the experimental group (3) OVX + E2 + EOI group, 80 μg/d E2 injection was started 7 d after OVX and EOI was applied 17 d after OVX. Bilateral masseter muscle mechanical withdrawal thresholds were measured before OVX, 7 days after OVX (before E2 injection), 17 days after OVX (10 days after E2 injection and before EOI) and 24 days after OVX (7 days after EOI). Immunofluorescence staining was used to reveal phospho-extracellular signal regulated kinase 1/2 (p-ERK1/2)-positive neurons in CA3 of hippocampus. The protein expression of p-ERK1/2 in hippocampus was detected using Western Blot.@*RESULTS@#Compared with the control group [left side: (135.3±8.5) g, right side: (135.4±10.8) g], bilateral masseter muscle mechanical withdrawal thresholds of OVX+E2 group [left side: (113.3±5.6) g, right side: (112.5 ± 5.6) g] and OVX+EOI group [left side: (93.3±5.4) g, right side: 90.8±5.5) g] were decreased (P < 0.01). Bilateral masseter muscle mechanical withdrawal thresholds were significantly lower in OVX+E2+EOI group [left side: (81.2±6.2) g, right side: 79.8±7.7) g] than in the control, OVX+E2 and OVX+EOI groups (P < 0.05). The proportion of p-ERK1/2 positive neurons in the CA3 region of the hippocampus was increased in the control, OVX+E2, OVX+EOI and OVX+E2+EOI groups in turn, and the difference between the groups was statistically significant (P < 0.05). p-ERK1/2 protein expression was increased in the control, OVX+E2 and OVX+EOI groups in turn, but the difference was not statistically significant (P>0.05). p-ERK1/2 expression was significantly higher in OVX+E2+EOI group than in the other three groups (P < 0.05).@*CONCLUSION@#High concentration of E2 could exacerbated EOI-induced chronic masseter hyperalgesia in ovariectomized rats, and its central mechanism may be related to the upregulation of the phosphorylation of ERK1/2 in hippocampus.

Effect of porous zirconia ceramics on proliferation and differentiation of osteoblasts / 北京大学学报(医学版)

OBJECTIVE@#To investigate the effect of porous surface morphology of zirconia on the proliferation and differentiation of osteoblasts.@*METHODS@#According to different manufacturing and pore-forming methods, the zirconia specimens were divided into 4 groups, including milled sintering group (M-Ctrl), milled porous group (M-Porous), 3D printed sintering group (3D-Ctrl) and 3D printed porous group (3D-Porous). The surface micromorphology, surface roughness, contact angle and surface elements of specimens in each group were detected by scanning electron microscope (SEM), 3D laser microscope, contact angle measuring device and energy-dispersion X-ray analysis, respectively. MC3T3-E1 cells were cultured on 4 groups of zirconia discs. The cell morphology of MC3T3-E1 cells on zirconia discs was eva-luated on 1 and 7 days by SEM. The cell proliferation was detected on 1, 3 and 5 days by cell counting kit-8 (CCK-8). After osteogenic induction for 14 days, the relative mRNA expression of alkaline phosphatase (ALP), type Ⅰ collagen (Colla1), Runt-related transcription factor-2 (Runx2) and osteocalcin (OCN) in MC3T3-E1 cells were detected by real-time quantitative polymerase chain reaction.@*RESULTS@#The pore size [(419.72±6.99) μm] and pore depth [(560.38±8.55) μm] of 3D-Porous group were significantly larger than the pore size [(300.55±155.65) μm] and pore depth [(69.97±31.38) μm] of M-Porous group (P < 0.05). The surface of 3D-Porous group appeared with more regular round pores than that of M-Porous group. The contact angles of all the groups were less than 90°. The contact angles of 3D-Ctrl (73.83°±5.34°) and M-Porous group (72.7°±2.72°) were the largest, with no significant difference between them (P>0.05). Cells adhered inside the pores in M-Porous and 3D-Porous groups, and the proliferation activities of them were significantly higher than those of M-Ctrl and 3D-Ctrl groups after 3 and 5 days' culture (P < 0.05). After 14 days' incubation, ALP, Colla1, Runx2 and OCN mRNA expression in 3D-Porous groups were significantly lower than those of M-Ctrl and 3D-Ctrl groups (P < 0.05). Colla1, Runx2 and OCN mRNA expressions in M-Porous group were higher than those of 3D-Porous group (P < 0.05).@*CONCLUSION@#The porous surface morphology of zirconia can promote the proliferation and adhesion but inhibit the differentiation of MC3T3-E1 cells.

Application of next-generation sequencing in detection of BRCA1/2 and homologous recombination repair pathway multi-genes germline mutation and correlation analysis / 中华预防医学杂志

Objective: To investigate the germline mutation status of related genes in breast cancer patients and high-risk individuals by next-generation sequencing. To analyze the correlations between homologous recombination repair (HR) pathway gene mutation status and clinicopathological characteristics of breast cancer patients. To supplement the database of breast cancer related gene mutations in Chinese population. Methods: This study is a cross-sectional study. From October 2020 to September 2021, whole blood samples were collected from 350 breast cancer patients and 49 high-risk individuals, admitted to Peking University People's Hospital and accepted genetic testing voluntarily. Germline mutations in 32 breast cancer related genes were detected by NGS. The clinicopathological characteristics, including age at the onset, family history, unilateral/bilateral tumor, Luminal typing (Luminal A subtype, Luminal B subtype, HER2-enriched subtype and triple negative breast cancer), tumor size and metastasis, were analyzed, and the correlations between HR pathway gene mutation status and clinicopathological characteristics were analyzed by Chi-squared test and Fisher's exact probability test. Results: Among 350 breast cancer patients, 64 (18.3%) cases carried gene pathogenic mutations (including pathogenic and likely pathogenic mutations), including 47 (13.4%) in BRCA1/2, 16 (4.6%) in non-BRCA1/2 genes, 1 (0.3%) in BRCA2 and FANCL. Among 49 high-risk individuals, 7 (14.3%) cases carried gene pathogenic mutations, including 6 (12.3%) in BRCA1/2 and 1 (2%) in ATM genes. BRCA1/2 pathogenic mutations were associated with age at the onset (18%, 8.7%, χ²=6.346, P=0.012), and the BRCA1/2 pathogenic mutation frequency was higher in patients diagnosed at age ≤45 years. HR pathway gene mutations (including pathogenic, likely pathogenic and uncertain significance mutations) were correlated with unilateral/bilateral tumor (49.5%, 68.4%, χ²=4.841, P=0.028) and Luminal typing (45.7%, 62.2%, 32%, 60%, χ²=12.004, P=0.007), and the HR mutation frequencies were higher in patients with bilateral tumor, Luminal B breast cancer and triple negative breast cancer (TNBC). Conclusion: The BRCA1/2 pathogenic mutation frequency in high-risk individuals is similar to that in breast cancer patients, and BRCA1/2 testing is helpful to guide breast cancer screening and prevention in high-risk individuals. Patients with early onset breast cancer, bilateral breast cancer, Luminal B breast cancer and TNBC have higher mutation frequencies of HR pathway genes, and HR pathway genes testing should be conducted as soon as possible to provide laboratory evidence for diagnosis, treatment, prognosis and risk evaluation of breast cancer.

Mechanisms and therapeutic drugs of high-altitude lung diseases / 药学实践杂志

The heavily harsh plateau environment including low pressure, hypoxia, cold, dryness and strong ultraviolet radiation, seriously threatens the physical and mental health of those who quickly enter the plateau area. Lungs are the sensitive organs for high altitude injury. High-altitude lung diseases include the acute high-altitude lung disease (i.e., high-altitude pulmonary edema), the chronic high-altitude lung disease (i.e., high-altitude pulmonary artery hypertension) and the high-altitude de-adapted reaction. This review summarizes the pathogenic mechanisms and the main therapeutic drugs of high-altitude lung diseases based on the recent research. Moreover, the related formulations and administration routes are also reviewed here. It will provide support and counsel for the diagnosis and treatment of high-altitude lung diseases.

A living cell-based fluorescent reporter for high-throughput screening of anti-tumor drugs / 药物分析学报

Suppression of cellular O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) can repress prolifera-tion and migration of various cancer cells,which opens a new avenue for cancer therapy.Based on the regulation of insulin gene transcription,we designed a cell-based fluorescent reporter capable of sensing cellular O-GlcNAcylation in HEK293T cells.The fluorescent reporter mainly consists of a reporter (green fluorescent protein (GFP)),an internal reference (red fluorescent protein),and an operator (neuronal differentiation 1),which serves as a "sweet switch" to control GFP expression in response to cellular O-GlcNAcylation changes.The fluorescent reporter can efficiently sense reduced levels of cellular O-GlcNAcylation in several cell lines.Using the fluorescent reporter,we screened 120 natural products and obtained one compound,sesamin,which could markedly inhibit protein O-GlcNAcylation in HeLa and human colorectal carcinoma-116 cells and repress their migration in vitro.Altogether,the present study demonstrated the development of a novel strategy for anti-tumor drug screening,as well as for con-ducting gene transcription studies.

Antibody-drug conjugates: Recent advances in linker chemistry

Antibody-drug conjugates (ADCs) are gradually revolutionizing clinical cancer therapy. The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects, and so has a major influence on the fate of ADCs. An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor. However, existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity. This defect is becoming an increasingly important factor that restricts the development of ADCs. The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers. The present review summarizes the advance of the chemical trigger, linker‒antibody attachment and linker‒payload attachment over the last 5 years, and describes the ADMET properties of ADCs. This work also helps clarify future developmental directions for the linkers.

Mechanism underlying mechanical stress regulating fibroblasts-derived exosomes at the osteotomized end following hallux valguscorrection / 中国组织工程研究

BACKGROUND: Bandage internal fixation (defined as the interphalangeal insertion of “8”-shaped bandage for elastic external fixation) produces a suitable mechanical environment for bone healing after minimally invasive treatment of hallux valgus. Stress stimulation is essential for bone healing after osteotomy, but the mechanism is still unclear OBJECTIVE: To study the regulatory mechanism of mechanical stress on fibroblasts-derived exosomes. METHODS: The medial bone tissue of the first metatarsal bone obtained in the surgery for hallux valgus was taken as a specimen. The fibroblasts were passaged in vitro via direct tissue adherent culture. The loading system provided a cell strain simulating external fixation using “8”-shaped bandage for the pressure-loading culture of hallux valgus fibroblasts, and then exosomes were extracted. Size distribution, morphology and markers of exosomes were detected by electron microscopy, nanoparticle tracking analysis and western blot assay. The study protocol was approved by the Ethics Committee of Wangjing Hospital of China Academy of Chinese Medical Sciences with approval No. 2013-03-21 on March 21, 2013. RESULTS AND CONCLUSION: Static stretching (15%) could promote the secretion of exosomes from fibroblasts. The expression of CD9 and CD81 was detected in the fibroblasts-derived exosomes of the control group and the experimental group. Range of exosome particle size distribution was consistent in the two groups of exosomes, and 15% static stretching increased the concentration of exosomes. This indicates that 15% static stretching helps fibroblasts secrete growth factors, which in turn contribute to osteoblast osteogenesis.

Abnormal eye movements in patients with idiopathic rapid eye movement sleep behavior disorder / 浙江大学学报·医学版

OBJECTIVE@#To analyze the characteristics of eye movements in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD).@*METHODS@#Twenty two patients with iRBD and 20 controls were enrolled between January 2017 and May 2019 from Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. Clinical data including polysomnogram (PSG) results were collected. Videonystagmography (VNG) including spontaneous nystagmus, gaze, saccade, tracking and optokinetic test were performed. The difference of VNG results between iRBD patients and controls were analyzed. The factors related to the abnormal VNG results were analyzed by using logistic regression analysis.@*RESULTS@#No significant differences were found between the iRBD and control groups in the spontaneous nystagmus, gaze nystagmus, square wave jerk, involuntary eye movement, saccade and optokinetic nystagmus (all >0.05). In smooth pursuit of 0.4-0.5 Hz and 0.6-0.7 Hz, iRBD patients had more type Ⅲ-Ⅳ curve than controls (=5.177 and 5.301, both <0.05). Logistic regression analysis indicated that less sleep time of N3 stage was related to the abnormal results in smooth pursuit of 0.4-0.5 Hz (=0.963, <0.05). iRBD patients with Ⅲ-Ⅳ type curve in smooth pursuit of 0.4-0.5 Hz had less N3 sleep time than iRBD patients with Ⅰ-Ⅱ type curve (52±28 min vs. 76±23 min, =2.197, <0.05).@*CONCLUSIONS@#Abnormal smooth pursuit was found in iRBD patients, which might be related to the pathological mechanism of iRBD.

Prophylactic anticoagulant therapy on portal vein thrombosis after laparoscopic splenectomy and pericardial devascularization / 中华普通外科杂志

Objective:To investigate the preventive effect and safety of prophylactic anticoagulant therapy with different doses on portal vein thrombosis after laparoscopic splenectomy and pericardial devascularization.Methods:109 hospitalized patients with portal hypertension undergoing laparoscopic procedures were divided into non preventive anticoagulant group(36 case), low dose prophylactic anticoagulant group(39 case), high dose preventive anticoagulant group(34 case). the incidence of portal vein thrombosis, the Yerdel greading, platelet count, APTT and bleeding complications were observed.Results:The incidence of portal vein thrombosis was 75%(27 cases), 49%(19 cases) and 29%(10 cases)respectively, (χ 2=14.719, P=0.001). There was no statistically significant difference among groups of postoperative platelet count[(569±46)×10 9/L, (565±42) ×10 9/L, (536±45)×10 9/L, F=0.074, P=0.909]; The level of D-dimer in the non-prophylactic anticoagulation group was significantly higher than that in the prophylactic anticoagulation groups[(6.35±1.24) mg/L, (2.97±0.48) mg/L, (2.13±0.38) mg/L, F=7.85, P=0.002]; The postoperative PT prolongation time in the prophylactic anticoagulation groups was longer than that in the non-prophylactic anticoagulation group[(18.5±0.7)s, (17.4±0.6)s, (12.7±0.2)s, F=30.88, P<0.001]. Conclusion:High dose prophylactic anticoagulation therapy can effectively reduce the incidence of portal vein thrombosis after laparoscopic splenectomy combined with pericardia devascularization without increasing the risk of postoperative bleeding.

Research progress of PET metabolic radiomics / 中华核医学与分子影像杂志

In recent years, the development of artificial intelligence technology has promoted the rise of radiomics, which makes image analysis tools, especially texture analysis, extensively concerned in image analysis of PET. In the study of radiomics, tools for image feature analysis such as texture analysis can extract rich information about pathological tissues from the imaging data to describe the characteristics of tumors, judge the prognosis, and evaluate the curative effect of tumors. This review mainly summarizes the research status, progress, challenges and foreground of texture analysis in PET metabolic radiomics.

Effect and possible mechanism of BMI-1 gene on radiosensitivity of human pancreatic cancer SW1990 cell line / 中华放射肿瘤学杂志

Objective:To evaluate the effect and possible mechanism of B-cell-specific moloney murine leukemia virus insertion site 1(BMI-1) on the radiosensitivity of pancreatic cancer SW1990 cell line.Methods:According to our previous study results, 4 Gy X-ray and down-regulation of BMI-1 expression were adopted as intervention conditions. The effect on the proliferation of SW1990 cells was assessed by clony formation assay. The effect on cell apoptosis and cell cycle was evaluated by flow cytometry. The effect upon the epithelial-mesenchymal transition (EMT) was determined by Western blot.Results:Clony formation assay and flow cytometry found that the lowest cell proliferation ability and the highest apoptotic rate were obtained after BMI-1 down-regulation and 4 Gy X-ray compared with other groups (all P<0.05). Flow cytometry revealed that the proportion of G 0/G 1 phase was significantly decreased, whereas the G 2/M phase was remarkably increased in pancreatic cancer stem cells treated with 4 Gy X-ray compared with the control group (both P<0.05). Nevertheless, opposite results were obtained after down-regulation of BMI-1 expression. Western blot showed that the expression of E-cadherin was up-regulated, whereas that of Vimentin was down-regulated following 4 Gy X-ray (both P<0.05). Conclusion:Downregulation of BMI-1 expression can enhance the radiosensitivity of pancreatic cancer SW1990 cells, and its mechanism may be related to cell cycle and EMT.